Abstract P5-04-02: Modulation of glucocorticoid receptor activity in invasive lobular carcinoma progression

Abstract

Abstract While considered a relatively uncommon breast cancer (BC) subtype, there are an estimated 39,000 new invasive lobular carcinoma (ILC) cases in the US yearly, making it the sixth most common among all tumor types. Yet, ILC remains understudied and, consequently, the mechanisms driving tumor growth and progression remain elusive. Hallmark E-Cadherin mutations resulting in defective cell-to-cell adhesion are believed to result in ILC’s single-file, discontinuous phenotype. ILC has also long been recognized for unique metastatic organotropism. Notably, its propensity to metastasize to serosal surfaces lining the gut (peritoneum) and lung (pleura) make it particularly challenging to diagnose and consequently is associated with an overall unfavorable prognosis. Indeed, ILC has significantly worse long-term prognosis than invasive ductal carcinoma (IDC) due to its poor response to endocrine therapy, and deadly, late occurring metastases. Thus, ILC patients are in dire need for improved therapies that can prevent tumor growth and progression five or more years after diagnosis. We previously found that selective GR modulators (SGRMs) that bind to the body's stress hormone receptor - the glucocorticoid receptor (GR) - can inhibit estrogen receptor positive (ER+) IDC growth in vivo. SGRMs are appealing clinically because they are (1) already in clinical trials and (2) well-tolerated by patients. Thus, SGRMs could be rapidly mobilized in the clinical setting if proven effective against ILC. We hypothesize that if SGRMs can slow ILC growth, as they do in IDC, GR modulation in ILC might improve patient outcome by slowing tumor growth and preventing serosal metastases. Using transcriptome data for 142 ILC tumors with long-term follow up clinical data from the METABRIC dataset we found a trend towards improved overall patient survival with increased NR3C1 (GR) expression. Our preliminary in vitro data also demonstrate slowed cell proliferation in an ILC cell line (MM134) relative to vehicle control. ILC cell lines have dramatically different adhesion preference for extracellular components of serosal surfaces. Preliminary transcriptome data lend insight into the proliferative and adhesive gene expression changes elicited by both ER and GR activation. We have found two CDK4/6 inhibitor-resistant GR+ ILC patient-derived organoids that may have GR-dependent proliferative and adhesive phenotypes. Future studies will use an in vivo mammary intraductal mouse model of metastatic colonization of distant organs to determine the role of tumor cell GR activation in proliferation and metastases to serosal surfaces. Citation Format: Candace Frerich, Ishrat Durdana, Sumanta Chatterjee, Ariella Hanker, Lynda Bennett, Carlos L. Arteaga, Suzanne D. Conzen. Modulation of glucocorticoid receptor activity in invasive lobular carcinoma progression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-04-02.